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Our group investigates the molecular basis of behaviour, in particular the ability to learn, to remember and to extinguish memories. Many aspects of behaviour depend on the ability to learn from experience. At the cellular level, this ability is reflected by the characteristics of the brain to undergo experience-dependent changes in synaptic connectivity and strength. Under pathophysiological conditions of the brain, dysfunctional learning and memory is often observed. Dysfunctional learning and memory can even lead to psychiatric disorders. Cognitive deficits are also a hallmark of neurodegenerative disorders. Understanding memory processing at the molecular level may point to targets of therapeutic interventions in order to ameliorate such disorders.
How do we learn and remember?
In the first research focus, we aim to get insights into mechanisms underlying
learning and memory, we use mice as a model system. Applying the so-called Cre/loxP
technology, mutants with tissue- and cell type-specific inactivation of genes
that are implicated in synaptic plasticity are generated and are analysed in
different behavioural tests, including learning and memory tests. Properties
of brain physiology are investigated with molecular, cell biological and electrophysiological
methods. Genes of interest are related
• to the endocannabinoid system (e.g. the cannabinoid receptor type 1;
CB1) (ref. 1),
• to the Ca2+/cAMP signalling system (e.g. CREB-binding protein) (ref.
2), and
• to intracellular kinases/phosphatases (e.g. Dyrk1A) (refs. 3, 4).
RNA interference is used as an additional tool to dissect cellular pathways necessary for synaptic plasticity.
What are the functions of the endocannabinoid system?
The second research focus resides in investigations on the various physiological
and pathophysiological roles of the endocannabinoid system (refs. 5, 6). This
recently discovered modulatory system appears to have important roles in maintaining
the body’s homeostasis. This is investigated regarding
(i) the extinction of aversive memories (refs 1, 4),
(ii) the control of excitability of neurons and neuroprotective properties (ref.
7-10),
(iii) feeding behaviour and energy metabolism (refs. 11, 12),
(iv) protection against inflammatory processes in the gastrointestinal tract
(ref. 13), and
(v) the control of proliferation and differentiation processes of neural progenitor
cells in the embryonic and adult brain.
References
1. Marsicano G, Wotjak CW, Azad SC, Bisogno T, Rammes G, Song T, Hofmann C,
Zieglgänsberger W, Di Marzo V, Lutz B (2002) The endogenous cannabinoid
system controls extinction of aversive memories. Nature 418:530-535.
2. Zhang Z, Hofmann C, Casanova E, Schütz G, Lutz B (2004) Generation of
a conditional allele of the CBP gene in mouse. Genesis 40:82-89.
3. Sitz JH, Tigges M, Baumgärtel K, Khaspekov LG, Lutz B (2004) Dyrk1A
potentiates steroid hormone-induced transcription via the chromatin remodeling
factor Arip4. Mol Cell Biol 24:5821-5834.
4. Cannich A, Wotjak C, Kamprath C, Lutz B, Marsicano G (2004). CB1 cannabinoid
receptors modulate kinase and phosphatase activity during extinction of conditioned
fear in mice. Learning & Memory, Learning & Memory 11:625-632.
5. Lutz B (2002) Molecular biology of cannabinoid receptors. Prostaglandins
Leukot Essent Fatty Acids 66:123-142. (Review)
6. Lutz B (2004) On-demand activation of the endocannabinoid system in the control
of neuronal excitability and epileptiform seizures. Biochem Pharm 68:1691-1998.
(Review)
7. Marsicano G, Goodenough S, Monory K, Hermann H, Eder M, Cannich A, Azad SC,
Grazia Cascio M, Ortega Gutiérrez S, van der Stelt M, Luz López-Rodriguez
M, Casanova E, Schütz G, Zieglgänsberger W, Di Marzo V, Behl C, Lutz
B (2003) CB1 cannabinoid receptors mediate on-demand defense against excitotoxicity.
Science 302:84-88.
8. Khaspekov LG, Brenz Verca MS, Frumkina LE, Hermann H, Marsicano G, Lutz B
(2004) Involvement of brain-derived neurotrophic factor in cannabinoid receptor-dependent
protection against excitotoxicity. Eur J Neurosci 19:1691-1698.
9. Bayatti N, Hermann H, Lutz B, Behl C. CRH-mediated induction of BDNF expression
is inhibited by the activation of the cannabinoid system. Endocrinology 146:1205-1213.
10. Marsicano G, Moosmann B, Hermann H, Behl C, Lutz B (2002) Neuroprotective
properties of cannabinoids against oxidative stress: role of the cannabinoid
receptor CB1. J Neurochem 80:448-456.
11. Cota D, Marsicano G, Tschöp M, Grübler Y, Flachskamm C, Schubert
M, Auer D, Thöne-Reinecke C, Ortmann S, Cervino C, Linthorst A, Pasquali
R, Lutz B, Stalla GK, Pagotto U (2003) Decreased fat mass in mice deficient
for cannabinoid receptor 1 is due to decreased orexigenic drive and impaired
adipocyte differentiation. J Clin Invest 112:423-431.
12. Marsicano G, Cota D, Stalla GK, Pasquali R, Pagotto U, Lutz B (2003) Cannabinoids
in energy balance and prospectives in the therapy of obesity. Curr Med Chem
CNS Agents 3:81-87. (Review)
13. Massa F, Marsicano G, Hermann H, Cannich A, Monory K, Cravatt BF, Ferri
G-L, Sibaev A, Storr M, Lutz B (2004) The endogenous cannabinoid system protects
against colonic inflammation. J Clin Invest 113:1202-1209.